“…This can be considered as translational relaxation or translational errors, which have been shown to be of relevance for the function of selenoenzymes, e.g. in response to pharmacological treatments with antibiotics of the aminoglycoside type [55], [56], [57], [58]. Here, we report that on average only 5.4±0.5 Sec residues per SELENOP molecule are present, and that a considerable inter-individual variation exists.…”
Section: Discussionmentioning
confidence: 71%
“…Alternatively, it has been shown before that the selenoprotein biosynthesis machinery is not always working very precisely and incorporation errors occur, e.g., in the presence of antibiotics [55], [56], [57], [58]. A more relaxed precision rate would also nicely explain the overall phenomenon that such an inefficient and slow process as Sec insertion still proceeds relatively fast despite the consecutive hurdles that are given by a total of successive 10 UGA codons in a single reading frame, as is the case in human SELENOP [61], [62].…”
Selenoprotein P (SELENOP) is a liver-derived transporter of selenium (Se) in blood, and a meaningful biomarker of Se status. Se is an essential trace element for the biosynthesis of enzymatically-active selenoproteins, protecting the organism from oxidative damage. The usage of uncalibrated assays hinders the comparability of SELENOP concentrations and their pathophysiological interpretation across different clinical studies. On this account, we established a new sandwich SELENOP-ELISA and calibrated against a standard reference material (SRM1950). The ELISA displays a wide working range (11.6–538.4 µg/L), high accuracy (2.9%) and good precision (9.3%). To verify whether SELENOP correlates to total Se and to SELENOP-bound Se, serum samples from healthy subjects and age-selected participants from the Berlin Aging Study II were analyzed by SELENOP-ELISA and Se quantification. SELENOP was affinity-purified and its Se content was determined from a subset of samples. There was a high correlation of total Se and SELENOP concentrations in young and elderly men, and in elderly women, but not in young women, indicating a specific sexual dimorphism in these biomarkers of Se status in young subjects. The Se content of isolated SELENOP was independent of sex and age (mean±SD: 5.4±0.5). By using this calibrated SELENOP-ELISA, prior reports on pathological SELENOP concentrations in diabetes and obesity are challenged as the reported values are outside reasonable limits. Biomarkers of Se status in clinical research need to be measured by validated assays in order to avoid erroneous data and incorrect interpretations, especially when analyzing young women. The Se content of circulating SELENOP differs between individuals and may provide some important diagnostic information on Se metabolism and status.
“…This can be considered as translational relaxation or translational errors, which have been shown to be of relevance for the function of selenoenzymes, e.g. in response to pharmacological treatments with antibiotics of the aminoglycoside type [55], [56], [57], [58]. Here, we report that on average only 5.4±0.5 Sec residues per SELENOP molecule are present, and that a considerable inter-individual variation exists.…”
Section: Discussionmentioning
confidence: 71%
“…Alternatively, it has been shown before that the selenoprotein biosynthesis machinery is not always working very precisely and incorporation errors occur, e.g., in the presence of antibiotics [55], [56], [57], [58]. A more relaxed precision rate would also nicely explain the overall phenomenon that such an inefficient and slow process as Sec insertion still proceeds relatively fast despite the consecutive hurdles that are given by a total of successive 10 UGA codons in a single reading frame, as is the case in human SELENOP [61], [62].…”
Selenoprotein P (SELENOP) is a liver-derived transporter of selenium (Se) in blood, and a meaningful biomarker of Se status. Se is an essential trace element for the biosynthesis of enzymatically-active selenoproteins, protecting the organism from oxidative damage. The usage of uncalibrated assays hinders the comparability of SELENOP concentrations and their pathophysiological interpretation across different clinical studies. On this account, we established a new sandwich SELENOP-ELISA and calibrated against a standard reference material (SRM1950). The ELISA displays a wide working range (11.6–538.4 µg/L), high accuracy (2.9%) and good precision (9.3%). To verify whether SELENOP correlates to total Se and to SELENOP-bound Se, serum samples from healthy subjects and age-selected participants from the Berlin Aging Study II were analyzed by SELENOP-ELISA and Se quantification. SELENOP was affinity-purified and its Se content was determined from a subset of samples. There was a high correlation of total Se and SELENOP concentrations in young and elderly men, and in elderly women, but not in young women, indicating a specific sexual dimorphism in these biomarkers of Se status in young subjects. The Se content of isolated SELENOP was independent of sex and age (mean±SD: 5.4±0.5). By using this calibrated SELENOP-ELISA, prior reports on pathological SELENOP concentrations in diabetes and obesity are challenged as the reported values are outside reasonable limits. Biomarkers of Se status in clinical research need to be measured by validated assays in order to avoid erroneous data and incorrect interpretations, especially when analyzing young women. The Se content of circulating SELENOP differs between individuals and may provide some important diagnostic information on Se metabolism and status.
“…Introduction of the construct by transfection into mammalian cells results in the translation of lacZ with termination at the UGA, but if the construct is altered by the addition of a SECIS element 3 to the coding sequences, readthrough occurs with the luciferase to -gal ratio reflecting readthrough efficiency and serving as a surrogate for selenoprotein synthesis. These and similar constructs established that the SECIS elements of selenoproteins contain the information for recognizing the UGA as selenocysteine and confirmed that the 3 -UTR sequences of selenoprotein mRNAs influence recoding efficiency in response to selenium availability [2,37,63,64]. A recent manuscript has applied this approach to all 25 human selenoprotein SECIS elements [65].…”
Section: -Utr Polymorphisms In Other Selenoprotein Mrnas Implicatedmentioning
There is considerable interest in the trace element selenium as a possible cancer chemopreventive dietary component, but supplementation trials have not indicated a clear benefit. Selenium is a critical component of selenium-containing proteins, or selenoproteins. Members of this protein family contain selenium in the form of selenocysteine. Selenocysteine is encoded by an in-frame UGA codon recognized as a selenocysteine codon by a regulatory element, the selenocysteine insertion sequence (SECIS), in the 3′-untranslated region of selenoprotein mRNAs. Epidemiological studies have implicated several selenoprotein genes in cancer risk or outcome based on associations between allelic variations and disease risk or mortality. These polymorphisms can be found in or near the SECIS or in the selenoprotein coding sequence. These variations both function to control protein synthesis and impact the efficiency of protein synthesis in response to the levels of available selenium. Thus, an individual’s genetic makeup and nutritional intake of selenium may interact to predispose them to acquiring cancer or affect cancer progression to lethality.
“…Figure 1.Mouse and human selenoprotein P. ( a ) Mouse Sepp1 after removal of the signal peptide. The N-terminal region includes the redox site [40–44], and heparin binding sites [79–86]. The Sec-rich C-terminal region includes the apoER2 binding site (dashed line: exact position unknown) and remaining Sec positions.…”
Section: Introductionmentioning
confidence: 99%
“…Given the complexity of the processes involved, caution emanating from studies of the ionic conditions and other features of tRNA (Sec) binding to membranes [36], and the potential for events associated with expression from the endogenous gene location being relevant, we altered relevant features of the native gene in mouse, and studied the consequences at the level of product present in plasma, and phenotype evident under either selenium replete or selenium-deficient diets. Relevantly, the efficiency of selenocysteine specification for a subset of selenoprotein mRNAs varies with stress levels and in several instances is influenced by selenium levels [35,37–40]. Though not studied here, it is also pertinent that under low selenium conditions UGAs in Sepp1 mRNA undertake some level of cysteine specification [41].…”
Dynamic redefinition of the 10 UGAs in human and mouse selenoprotein P (Sepp1) mRNAs to specify selenocysteine instead of termination involves two 3′ UTR structural elements (SECIS) and is regulated by selenium availability. In addition to the previously known human Sepp1 mRNA poly(A) addition site just 3′ of SECIS 2, two further sites were identified with one resulting in 10–25% of the mRNA lacking SECIS 2. To address function, mutant mice were generated with either SECIS 1 or SECIS 2 deleted or with the first UGA substituted with a serine codon. They were fed on either high or selenium-deficient diets. The mutants had very different effects on the proportions of shorter and longer product Sepp1 protein isoforms isolated from plasma, and on viability. Spatially and functionally distinctive effects of the two SECIS elements on UGA decoding were inferred. We also bioinformatically identify two selenoprotein S mRNAs with different 5′ sequences predicted to yield products with different N-termini. These results provide insights into SECIS function and mRNA processing in selenoprotein isoform diversity.
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